The antiproliferative ELF2 isoform, ELF2B, induces apoptosis in vitro and perturbs early lymphocytic development in vivo.
ELF2 (E74-like factor 2) also known as NERF (new Ets-related factor), a member of the Ets family of transcription factors, regulates genes important in B and T cell development, cell cycle progression, and angiogenesis. Conserved ELF2 isoforms, ELF2A, and ELF2B, arising from alternative promoter usage can exert opposing effects on target gene expression. ELF2A activates, whilst ELF2B represses, gene expression, and the balance of expression between these isoforms may be important in maintaining normal cellular function. We compared the function of ELF2 isoforms ELF2A and ELF2B with other ELF subfamily proteins ELF1 and ELF4 in primary and cancer cell lines using proliferation, colony-forming, cell cycle, and apoptosis assays. We further examined the role of ELF2 isoforms in haemopoietic development using a Rag1 -/-murine bone marrow reconstitution model. ELF2B overexpression significantly reduced cell proliferation and clonogenic capacity, minimally disrupted cell cycle kinetics, and induced apoptosis. In contrast, ELF2A overexpression only marginally reduced clonogenic capacity with little effect on proliferation, cell cycle progression, or apoptosis. Deletion of the N-terminal 19 amino acids unique to ELF2B abrogated the antiproliferative and proapoptotic functions of ELF2B thereby confirming its crucial role. Mice expressing Elf2a or Elf2b in haemopoietic cells variously displayed perturbations in the pre-B cell stage and multiple stages of T cell development. Mature B cells, T cells, and myeloid cells in steady state were unaffected, suggesting that the main role of ELF2 is restricted to the early development of B and T cells and that compensatory mechanisms exist. No differences in B and T cell development were observed between ELF2 isoforms. We conclude that ELF2 isoforms are important regulators of cellular proliferation, cell cycle progression, and apoptosis. In respect to this, ELF2B acts in a dominant negative fashion compared to ELF2A and as a putative tumour suppressor gene. Given that these cellular processes are critical during haemopoiesis, we propose that the regulatory interplay between ELF2 isoforms contributes substantially to early B and T cell development.


Sexual dysfunction in patients treated with atypical antipsychotics.
Atypical antipsychotics can provide improvement in schizophrenic symptomatology but also may cause side effects, such as erectile dysfunction and decreased libido, which can be problematic for patients. In order to keep patients symptomatically stable and to help alleviate these side effects, clinicians should alter the treatment strategy, possibly by switching medications, to encourage adherence to the medication as well as optimize patients' outcomes. To establish clinically useful standards for switching agents, more studies are needed that focus on gradual cross-titration methods to achieve therapeutic doses for patients.


[Effect of DNA-tropic antineoplastic and antiparasitic agents on DNAase I activity].
Kinetics of DNAase I activity was studied in reaction mixtures containing tightly bound to DNA drugs used for study and treatment of cancer and some other diseases. Distamycin proved to be the strongest inhibitor. The inhibitory activity of the substances studied decreased as follows: distamycin greater than or equal to actinomycin D greater than or equal to ethidium bromide > proflavine > carminomycin > bleomycin. The latter substance did not possess any inhibitory action. The data obtained are discussed in relation to mechanisms of interaction of the substances studied and DNA. High efficiency was typical for substances, which were bound with the DNA molecules on their small curvature.


PARP inhibitor rucaparib induces changes in NAD levels in cells and liver tissues as assessed by MRS.
Poly(adenosine diphosphate ribose) polymerases (PARPs) are multifunctional proteins which play a role in many cellular processes. Namely, PARP1 and PARP2 have been shown to be involved in DNA repair, and therefore are valid targets in cancer treatment with PARP inhibitors, such as rucaparib, currently in clinical trials. Proton magnetic resonance spectroscopy (1 H-MRS) was used to study the impact of rucaparib in vitro and ex vivo in liver tissue from mice, via quantitative analysis of nicotinamide adenosine diphosphate (NAD+ ) spectra, to assess the potential of MRS as a biomarker of the PARP inhibitor response. SW620 (colorectal) and A2780 (ovarian) cancer cell lines, and PARP1 wild-type (WT) and PARP1 knock-out (KO) mice, were treated with rucaparib, temozolomide (methylating agent) or a combination of both drugs. 1 H-MRS spectra were obtained from perchloric acid extracts of tumour cells and mouse liver. Both cell lines showed an increase in NAD+ levels following PARP inhibitor treatment in comparison with temozolomide treatment. Liver extracts from PARP1 WT mice showed a significant increase in NAD+ levels after rucaparib treatment compared with untreated mouse liver, and a significant decrease in NAD+ levels in the temozolomide-treated group. The combination of rucaparib and temozolomide did not prevent the NAD+ depletion caused by temozolomide treatment. The 1 H-MRS results show that NAD+ levels can be used as a biomarker of PARP inhibitor and methylating agent treatments, and suggest that in vivo measurement of NAD+ would be valuable.


Analysis of Serum IgG1 to Predict Progression and Therapeutic Effect in Patients with Multiple Myeloma.
The correlation between laboratory indicators and clinical treatment effects and the prognosis of multiple myeloma remains poorly understood. Therefore, our study investigated whether serum IgG subclasses could be employed as potential indicators contributed to evaluate the therapeutic effect and prognosis of patients with multiple myeloma. Patients and Methods. Records of patients with multiple myeloma were initially diagnosed at the First Affiliated Hospital of Soochow University, China, from August 1, 2017, to February 28, 2020. The assessment abilities of serological indicators for therapeutic effect were evaluated in patients compared with healthy controls. In 560 study patients with multiple myeloma, serum IgA, IgG, IgM, κ-LC, and λ-LC increased by15%, 33.04%, 1.96%, 27.50%, and 26.43%, respectively. Further analysis found that IgG1, IgG2, IgG3, and IgG4 were over the upper limit of the reference range with 26.38%, 6.09%, 8.12%, and 4.64%, respectively. κ-LC and λ-LC were found in the urine in 65.13% and 29.70%, respectively. In peripheral blood, the proportion of CD3+CD4+, CD3-CD19+ cells, and CD4+/CD8+ decreased, whereas CD3+CD8+ cells and CD16+/CD56+ increased, and the associated cytokines IL-2, IL-4, IL-6, TNF-α, and IFN-γ were upregulated in patients when compared with healthy controls. Furthermore, the serum levels of IgA, IgG, IgG1, IgG2, IgG3, and IgG4 gradually decreased in patients before, during, and after treatment. Similar results were found in serum and urine κ-LC and λ-LC. Serum IgG1 level could serve as the potential indicator for evaluating the therapeutic effect for patients with multiple myeloma. κ-LC and λ-LC also have the potential to be prognostic indicators. More studies are warranted to explore these serological indicators for personalized therapy in the future.


Impact of global feminist film curriculum on medical student engagement in women's health.
Film effectvely imparts experiential knowledge of lived experiences especially in cross-cultural settings. Incorporating film into medical education can catalyze awareness of global issues in women's health. Film-based interventions highlighting such topics have not been reported in literature. This study outlines one session of an 8-week elective course for trainees to engage with topics in women's health through global cinema. Quantitative and qualitative data were collected from participants during each session and via post-session surveys. Class discussions and survey data reflected favorable responses and positive engagement with the pre-session film viewings and 75-minute weekly discussions. A feminist, film-based curriculum for medical and graduate students may broaden trainees' knowledge of global women's health. In medical education, film may serve as an effective tool to encourage a life-course and gender equity approach to women's health topics, rather than more traditional sexual-reproductive framings.


Ultrastructure and birefringence of the isolated mitotic apparatus of marine eggs.
Isolated mitotic apparatuses (MA) of clam and sea urchin eggs were investigated by polarizing and electron microscopy. Examination of fixed MA in oils of different refractive index revealed that at least 90% of the retardation of isolated MA is due to positive, form birefringence, the remaining retardation deriving from positive, intrinsic birefringence. Electron micrographs reveal the isolated MA to be composed of microtubules, ribosome-like particles, and a variety of vesicles. In the clam MA the number of vesicles and ribosome-like particles relative to the number of microtubules is much lower than in the sea urchin MA. In clam MA this allows form and intrinsic birefringence to be related directly to microtubules. The relation of birefringence to microtubules in isolated sea urchin MA is more complex since ribosome-like particles adhere to microtubules, are oriented by them, and are likely to contribute to the form birefringence of the isolated MA. However, comparison of values of retardation for clam and sea urchin MA, indicates that the major part of the birefringence in sea urchin MA is also due to microtubules. The interpretation of the structures giving rise to birefringence in the MA of the living cells is likely to be even more complex since masking substances, compression, or tension on the living MA may alter the magnitude or sign of the birefringence.


The role of philosophy in public policy and bioethics: introduction.
As various societies have created public commissions to help develop proposals for public policies relating to issues in bioethics, philosophers have sometimes been called upon to serve on the staff of, or to provide consultation to, these public bodies. This issue of the Journal is devoted to examining problems that arise as one tries to articulate the proper role of philosophers serving in these capacities. It includes articles by Frances M. Kamm ("The philosopher as insider and outsider"), Martin Benjamin ("Philosophical integrity and policy development in bioethics"), Richard W. Momeyer ("Philosophers and the public policy process: inside, outside, or nowhere at all?"), Paul T. Menzel ("Public philosophy: distinction without authority"), and E. Haavi Morreim (Physician investment and self-referral: philosophical analysis of a contentious debate").


Severe ocular side effects of perhexilene maleate: case report.
We report a case of perhexilene maleate (PEXID) toxicity in which the presenting feature was loss of vision secondary to chronic papilloedema. Vortex keratopathy similar to that seen in amiodarone keratopathy was present, and corneal and conjunctival biopsy findings are presented. To our knowledge this is the first case report of a keratopathy occurring in perhexilene toxicity. After withdrawal of the drug the papilloedema and keratopathy subsided, but some visual deficit remains. The properties of perhexilene maleate and other amphiphilic drugs are described, and the possible aetiology of vortex keratopathy is discussed.


Systematic binding analysis of the insulin gene transcription control region: insulin and immunoglobulin enhancers utilize similar transactivators.
The 5' regulatory region (-345 to +1) of the rat insulin I gene (Ins-I) was examined for binding to cellular factors with short oligodeoxynucleotide probes. Over 40 binding species were detected. The binding profiles were specific for each cell type studied. We characterized the factors binding two elements crucial for enhancer activity (the Nir and Far boxes) which bear sequence similarity to the microE1, microE2, and microE3 elements of the immunoglobulin heavy-chain enhancer. The Nir box binds three cellular factors that display preferential affinities for microE1, microE2, or microE3, and the Far box binds two factors related to microE2 or microE3. The insulin gene enhancer was mutated at the Nir box element to reflect the sequences of microE1, microE2, or microE3. Ins-microE2 was fully active, Ins-microE3 was partially active, and Ins-microE1 was inactive. Thus, factors similar or identical to nuclear factor NF-microE1, NF-microE2, or NF-microE3 may play a role in the activity of the insulin gene enhancer.


N-glycolylneuraminic acid xenoantigen contamination of human embryonic and mesenchymal stem cells is substantially reversible.
Human embryonic and mesenchymal stem cell therapies may offer significant benefit to a large number of patients. Recently, however, human embryonic stem cell lines cultured on mouse feeder cells were reported to be contaminated by the xeno-carbohydrate N-glycolylneuraminic acid (Neu5Gc) and considered potentially unfit for human therapy. To determine the extent of the problem of Neu5Gc contamination for the development of stem cell therapies, we investigated whether it also occurs in cells cultured on human feeder cells and in mesenchymal stem cells, what are the sources of contamination, and whether the contamination is reversible. We found that N-glycolylneuraminic acid was present in embryonic stem cells cultured on human feeder cells, correlating with the presence of Neu5Gc in components of the commercial serum replacement culture medium. Similar contamination occurred in mesenchymal stem cells cultured in the presence of fetal bovine serum. The results suggest that the Neu5Gc is present in both glycoprotein and lipid-linked glycans, as detected by mass spectrometric analysis and monoclonal antibody staining, respectively. Significantly, the contamination was largely reversible in the progeny of both cell types, suggesting that decontaminated cells may be derived from existing stem cell lines. Although major complications have not been reported in the clinical trials with mesenchymal stem cells exposed to fetal bovine serum, the immunogenic contamination may potentially be reflected in the viability and efficacy of the transplanted cells and thus bias the published results. Definition of safe culture conditions for stem cells is essential for future development of cellular therapies.


Handling a pediatric transport.
When minutes matter, being prepared can pave the way to a happier ending in heartrending situations. This article describes how to prepare for and handle transport of a critically ill or injured child.


[The relationship between smoking status and epidermiology of asthma in people aged over 14 years in China].
Objective: To study the relationship between bronchial asthma and smoking status in Chinese people. Methods: Asthma epidemiological survey and stratified-cluster-random method survey were performed in residents over 14 years in 8 provinces (cities) of China from February 2010 to August 2012. Asthma was diagnosed based upon case history, clinical signs and lung function test. Smoking status was investigated by questionnaire. Results: Sampling population was 180 099 and 164 215 were valid. A total of 2 034 subjects were diagnosed as asthma including 79 692 men and 84 523 women. The overall prevalence rate of asthma was 1.24% (2 034/164 215). Smokers were 23.8% (39 137/164 215) in the whole population. Smokers were 34.5% (702/2 034) in asthmatic patients, compared with 23.7% (38 435/162 181) in no-asthmatic population. The incidence of asthma was 1.79% and 1.06% in smokers and non-smokers respectively (P<0.001), suggesting that OR of smoking was 1.70 (95% CI 1.55-1.86, P<0.001). According to asthma control test (ACT) score, the level of asthma control in non smoking group was higher than that in smoking group(43.2% vs 35.3%). The times of hospitalization due to acute exacerbations(0.51 vs 0.41 events/person/year), total hospitalization rate(27.35% vs 20.12%), annual emergency room visits (0.80 vs 0.60 events/person/year) and emergency room visit rate (31.77% vs 24.47%) were all much higher in smoking asthmatic patients than those in non smoking asthmatic patients, indicating that the level of asthma control in smoking patients was significantly worse than in non smoking patients. Conclusions: The smoking rate in Chinese people over 14 years is still high. The prevalence rate of asthma in smokers is significantly higher than that of non-smokers. The level of asthma control in smokers is significantly worse than that in non smokers.


Back pain rehabilitation.
Back pain is a universal problem that becomes persistent in 5-10% of patients following an acute episode. This makes it one of the most costly areas of health care in Australia. This article outlines the paradigm that general practitioners should adopt to assist the patient to live with their pain experience. The development of persistent back pain is not a static process but one that is heavily influenced by the context in which it occurs. Patient characteristics, health care providers and the health system environment contribute and interact to promote the development of persistent pain. Health care providers involved in managing persistent pain should remain confidant, positive and reassuring. They should encourage activity, discourage fear avoidance behaviour, and consider rehabilitation early before illness beliefs become entrenched. Multidisciplinary rehabilitation, when used early, aims to improve function and assist in the return to work process; when used late, it aims to prevent worsening disability and increased coping for patients.


Strain-specific Plasmodium falciparum growth inhibition among Malian children immunized with a blood-stage malaria vaccine.
The blood-stage malaria vaccine FMP2.1/AS02A, comprised of recombinant Plasmodium falciparum apical membrane antigen 1 (AMA1) and the adjuvant system AS02A, had strain-specific efficacy against clinical malaria caused by P. falciparum with the vaccine strain 3D7 AMA1 sequence. To evaluate a potential correlate of protection, we measured the ability of participant sera to inhibit growth of 3D7 and FVO strains in vitro using high-throughput growth inhibition assay (GIA) testing. Sera from 400 children randomized to receive either malaria vaccine or a control rabies vaccine were assessed at baseline and over two annual malaria transmission seasons after immunization. Baseline GIA against vaccine strain 3D7 and FVO strain was similar in both groups, but more children in the malaria vaccine group than in the control group had 3D7 and FVO GIA activity ≥15% 30 days after the last vaccination (day 90) (49% vs. 16%, p<0.0001; and 71.8% vs. 60.4%, p = 0.02). From baseline to day 90, 3D7 GIA in the vaccine group was 7.4 times the mean increase in the control group (p<0.0001). In AMA1 vaccinees, 3D7 GIA activity subsequently returned to baseline one year after vaccination (day 364) and did not correlate with efficacy in the extended efficacy time period to day 730. In Cox proportional hazards regression models with time-varying covariates, there was a slight suggestion of an association between 3D7 GIA activity and increased risk of clinical malaria between day 90 and day 240. We conclude that vaccination with this AMA1-based malaria vaccine increased inhibition of parasite growth, but this increase was not associated with allele-specific efficacy in the first malaria season. These results provide a framework for testing functional immune correlates of protection against clinical malaria in field trials, and will help to guide similar analyses for next-generation malaria vaccines. Clinical trials registry: This clinical trial was registered on clinicaltrials.gov, registry number NCT00460525.


Self-report measures of family functioning: extensions of a factorial analysis.
A factor analysis of four commonly used self-report measures of family functioning (Bloom, 1985) yielded 15 5-item factors. Five of these item sets have now been revised and strengthened. These modifications were undertaken because a review of the literature has revealed that the results of the factor analysis are being increasingly used in family studies. The rationale and description of the revisions of the factor item sets are presented. Psychometric analysis of the revised factors suggests that factor scores are highly reliable as well as stable over time. In addition to presenting comprehensive reliability data, this article provides information regarding factor score intercorrelations and structure, as well as a commentary on the factors themselves.


Indicators to control drug costs in hospitals.
A set of monthly indicators that can be used to track hospital drug costs is described; use of the indicators is illustrated using data from one hospital pharmacy department. Weighted for the top 100 drug products' contribution to drug expenditures, the drug-cost inflation index identifies changes in the price of drug products, and the drug-cost index accounts for changes attributed to newly marketed drug products and changes in drug use. Pharmacologic-cost indicators represent the expenditure for drug products in specific pharmacologic classifications per patient day, and disease-drug cost indicators represent the expenditure per day for drugs used to treat patients with specific diseases. Other indicators are the drug cost per patient day, per outpatient clinic visit, and per outpatient prescription. Indicators of intravenous solution cost per patient day, contrast media cost per radiologic procedure, and radiopharmaceuticals cost per procedure are described. Hospital pharmacy directors can use the indicators to develop accurate drug budgets and to monitor changes in drug costs on a routine basis; the indicators also can provide useful information in monitoring drug costs for diagnosis-related groups.


Protein kinase Cι promotes UBF1-ECT2 binding on ribosomal DNA to drive rRNA synthesis and transformed growth of non-small-cell lung cancer cells.
Epithelial cell-transforming sequence 2 (ECT2) is a guanine nucleotide exchange factor for Rho GTPases that is overexpressed in many cancers and involved in signal transduction pathways that promote cancer cell proliferation, invasion, and tumorigenesis. Recently, we demonstrated that a significant pool of ECT2 localizes to the nucleolus of non-small-cell lung cancer (NSCLC) cells, where it binds the transcription factor upstream binding factor 1 (UBF1) on the promoter regions of ribosomal DNA (rDNA) and activates rDNA transcription, transformed cell growth, and tumor formation. Here, we investigated the mechanism by which ECT2 engages UBF1 on rDNA promoters. Results from ECT2 mutagenesis indicated that the tandem BRCT domain of ECT2 mediates binding to UBF1. Biochemical and MS-based analyses revealed that protein kinase Cι (PKCι) directly phosphorylates UBF1 at Ser-412, thereby generating a phosphopeptide-binding epitope that binds the ECT2 BRCT domain. Lentiviral shRNA knockdown and reconstitution experiments revealed that both a functional ECT2 BRCT domain and the UBF1 Ser-412 phosphorylation site are required for UBF1-mediated ECT2 recruitment to rDNA, elevated rRNA synthesis, and transformed growth. Our findings provide critical molecular insight into ECT2-mediated regulation of rDNA transcription in cancer cells and offer a rationale for therapeutic targeting of UBF1- and ECT2-stimulated rDNA transcription for the management of NSCLC.


What works in promoting and maintaining diversity in nursing programs.
The presence of a registered nurse (RN) workforce that is culturally and linguistically familiar with underrepresented minorities promotes effective health care for patients. A lack of diversity in the nursing education pipeline has led to a lack of diversity among registered nurses. This qualitative descriptive study explored faculty perceptions of factors that attracted and maintained a diverse nursing student body at three different universities with large percentages of minority students. Websites were evaluated for diversity and audio-taped telephone interviews were conducted with nursing faculty using a semistructured set of open-ended questions. College location, online courses, community outreach programs, the presence of a diverse faculty and students, faculty accessibility, and financial aid with low college costs were identified as common factors in attracting and retaining minority students. Barriers included the cost for low socioeconomic status students, inadequate primary and secondary educational preparation, inherent bias in the institution, competition from other schools, admission policies, and limited diversity in leadership and faculty. Commitment to improving and maintaining diversity in nursing programs requires a sustained faculty effort to make the programs fit for the minority student.


Characterization of Biomolecular Helices and Their Complementarity Using Geometric Analysis.
A general method is presented to characterize the helical properties of potentially irregular helices, such as those found in protein secondary and tertiary structures and nucleic acids. The method was validated using artificial helices with varying numbers of points, points per helical turn, pitch, and radius. The sensitivity of the method was validated by applying increasing amounts of random perturbation to the coordinates of these helices; 399 360 helices in total were evaluated. In addition, the helical parameters of protein secondary structure elements and nucleic acid helices were analyzed. Generally, at least seven points were required to recapitulate the parameters of a helix using our method. The method can also be used to calculate the helical parameters of nucleic acid-binding proteins, like TALE, enabling direct analysis of their helix complementarity to sequence-dependent DNA distortions.


Modulation of extrasynaptic GABAA alpha 5 receptors in the ventral hippocampus normalizes physiological and behavioral deficits in a circuit specific manner.
Hippocampal hyperactivity is correlated with psychosis in schizophrenia patients and likely attributable to deficits in GABAergic signaling. Here we attempt to reverse this deficit by overexpression of the α5-GABAA receptor within the ventral hippocampus (vHipp). Indeed, this is sufficient to normalize vHipp activity and downstream alterations in dopamine neuron function in the MAM rodent model. This approach also attenuated behavioral deficits in cognitive flexibility. To understand the specific pathways that mediate these effects, we used chemogenetics to manipulate discrete projections from the vHipp to the nucleus accumbens (NAc) or prefrontal cortex (mPFC). We found that inhibition of the vHipp-NAc, but not the vHipp-mPFC pathway, normalized aberrant dopamine neuron activity. Conversely, inhibition of the vHipp-mPFC improved cognitive function. Taken together, these results demonstrate that restoring GABAergic signaling in the vHipp improves schizophrenia-like deficits and that distinct behavioral alterations are mediated by discrete projections from the vHipp to the NAc and mPFC.


Genetic and environmental influences on obsessive-compulsive behaviour across development: a longitudinal twin study.
Little is known about the factors influencing the stability of obsessive-compulsive behaviour (OCB) from childhood to adolescence. The current study aimed to investigate: (1) the stability of paediatric OCB over a 12-year period; (2) the extent to which genetic and environmental factors influence stability; and (3) the extent to which these influences are stable or dynamic across development. The sample included 14 743 twins from a population-based study. Parental ratings of severity of OCB were collected at ages 4, 7, 9 and 16 years. OCB was found to be moderately stable over time. The genetic influence on OCB at each age was moderate, with significant effects also of non-shared environment. Genetic factors exerted a substantial influence on OCB persistence, explaining 59-80% of the stability over time. The results indicated genetic continuity, whereby genetic influences at each age continue to affect the expression of OCB at subsequent ages. However, we also found evidence for genetic attenuation in that genetic influences at one age decline in their influence over time, and genetic innovation whereby new genes 'come on line' at each age. Non-shared environment influenced stability of OCB to a lesser extent and effects were largely unique to each age and displayed negligible influences on OCB at later time points. OCB appears to be moderately stable across development, and stability is largely driven by genetic factors. However, the genetic effects are not entirely constant, but rather the genetic influence on OCB appears to be a developmentally dynamic process.


Grading disorder severity and averted burden by access to treatment within the GBD framework: a case study with anxiety disorders.
The Global Burden of Disease Study (GBD) estimates burden by cause with major relevance for resource allocators globally. Non-fatal burden estimates are influenced by disorder severity. However, for many disorders, global severity is sourced from a single high-income country survey. We aimed to estimate severity distributions that vary by Healthcare Access Quality Index (HAQI) using anxiety disorders as a case study and present the usefulness of this method in simulating averted and avoidable burden globally. In this case study, we estimated treatment use among respondents with anxiety disorder in the 1997 Australian National Survey of Mental Health and Wellbeing (NSMHWB), the source used to estimate severity of anxiety disorders in GBD. Treatment effects were sourced from the Cochrane Database of Systematic Reviews and pooled via network meta-analysis. Severity distribution was established via a meta-regression of their disability weights, derived from 12-item short form survey scores. We simulated the shift in severity across scenarios without access to treatment and with full access to optimal treatment (cognitive behavioural therapy and antidepressants). We interpolated this shift linearly along the HAQI, extrapolated country-specific severity from HAQI scores, and calculated averted and avoidable burden. The database review sourced 56 reviews, of which eight were eligible for inclusion. These eight reviews reported on 156 randomised controlled trials, with 194 treatment effects. Respondents to the 1997 NSMHWB consisted of 5936 women (55·8%) and 4705 (44·2%) men aged 18 years or older (mean age and ethnicity data not available). The survey-weighted treatment effect size was -0·28 (95% uncertainty interval -0·45 to -0·12). The pooled treatment effect for full coverage optimal treatment was -1·07 (-1·47 to -0·64). The sequela-weighted disability weight among people with anxiety disorder in the NSMHWB was 0·141 (0·042 to 0·275). The estimated disability weight was 0·188 (0·070 to 0·341) after removing the benefits of treatment and 0·056 (0·013 to 0·140) after providing all people with anxiety disorder access to optimal treatment. Globally, 12·5% (4·6 to 21·5) of anxiety disorder burden was averted because of available treatment. However, 71·1% (46·2 to 87·6) of global anxiety disorder burden could be averted if all people with anxiety disorders had access to optimal treatment. Because it is based on guidance from a single survey done in one high-income country, the burden of anxiety disorders in low-income and middle-income countries is probably underestimated by GBD. Despite the availability of effective treatments, low use of these treatments means that most burden is still avoidable. Most of the burden could be averted if all people with anxiety disorders had access to optimal treatment, highlighting the importance of public promotion and referral pathways of treatment for anxiety disorders. Location-specific severity distributions in GBD would greatly increase precision in burden estimates and highlight avertable burden to clinicians, public health practitioners, and policy makers. Queensland Health and Bill & Melinda Gates Foundation.


Long-term Complications after facial trauma: literature review.
Long-term complications after facial trauma: literature review. In facial trauma medicine, many articles deal with necessary treatment in an acute setting to achieve the best possible functional and aesthetic outcome for the patient. It is difficult, if not impossible, to ensure long-term follow-up with these patients. Often the long-term outcome is not reported and, if so, most data are retrospective. The goal of this article is to present an overview of known data concerning complications after the initial healing processes are completed. Literature review Results: An overview of complications is presented and discussed. Comparison of results is not possible due to the large number of factors influencing outcome (age, multiple injuries, severity of trauma, etc.). Post-trauma complications are inevitable, but it is agreed that, in any case, the initial treatment of trauma is important in determining optimal functional and aesthetic outcomes. Close collaboration between different specialisms is essential to achieve good patient management, control and follow-up. Long-term post-trauma complications are inevitable, but it is important to be aware of these complications so as to provide the best possible treatment.


Analysis of the 148Gd and 154Dy Content in Proton-Irradiated Lead Targets.
This work presents the determination of the 148Gd and 154Dy content in Pb targets irradiated by 220-2600 MeV protons. It includes the chemical separation of lanthanides, followed by the preparation of proper samples, by molecular plating technique, for α-spectrometry measurements. The experimental cross section results were compared with theoretical predictions, calculated with the INCL++-ABLA07 code. The comparisons showed a satisfactory agreement for 148Gd (less than within a factor two), while measured 154Dy cross sections are higher than the theoretical values.


Direct visualization of intestinal villi by high-resolution magnifying upper endoscopy: a validation study.
New generation videoendoscopes potentially may visualize duodenal villi. This study compared endoscopic findings with this type of instrument to the histopathologic evaluation of duodenal villi. A total of 191 patients underwent upper endoscopy for the purpose of obtaining duodenal biopsy specimens. The findings were assessed independently by 3 experienced observers by using a commercially available, high-resolution, high-magnifying (x2) videoendoscope. The duodenal villous profile was determined by endoscopic magnification and by endoscopic magnification after filling the duodenum with water. With both endoscopic magnification and endoscopic magnification after filling the duodenum with water, villous patterns were scored as the following: definitely present, partially present, or definitely absent. Villous patterns also were histopathologically scored as the following: normal, partial villous pattern, or total villous atrophy. Interobserver variability was excellent (kappa = 0.93). The concordance between either endoscopic magnification or endoscopic magnification after filling the duodenum with water and histology was 100% for presence/absence of villi. The sensitivity, the specificity, and the positive and negative predictive values of endoscopic magnification for detection of any villous abnormality were 95%, 99%, 95%, and 99%, respectively; the respective values of endoscopic magnification after filling the duodenum with water were 95%, 98%, 92%, and 99%. High-resolution magnifying upper endoscopy can reliably predict the presence or the absence of duodenal villi.


The Therapeutic Value of Solanum Steroidal (Glyco)Alkaloids: A 10-Year Comprehensive Review.
Steroidal (glycol)alkaloids S(G)As are secondary metabolites made of a nitrogen-containing steroidal skeleton linked to a (poly)saccharide, naturally occurring in the members of the Solanaceae and Liliaceae plant families. The genus Solanum is familiar to all of us as a food source (tomato, potato, eggplant), but a few populations have also made it part of their ethnobotany for their medicinal properties. The recent development of the isolation, purification and analysis techniques have shed light on the structural diversity among the SGAs family, thus attracting scientists to investigate their various pharmacological properties. This review aims to overview the recent literature (2012-2022) on the pharmacological benefits displayed by the SGAs family. Over 17 different potential therapeutic applications (antibiotic, antiviral, anti-inflammatory, etc.) were reported over the past ten years, and this unique review analyzes each pharmacological effect independently without discrimination of either the SGA's chemical identity or their sources. A strong emphasis is placed on the discovery of their biological targets and the subsequent cellular mechanisms, discussing in vitro to in vivo biological data. The therapeutic value and the challenges of the solanum steroidal glycoalkaloid family is debated to provide new insights for future research towards clinical development.


[Intermediate-risk gastrointestinal stromal tumor: diagnosis through hydrogastric ultrasonography].
Evaluation of submucosal lesions of the digestive tract with conventional endoscopy is unsatisfactory since this technique does not allow direct observation or correct evaluation of the size and layer of origin of the tumor; therefore, in most patients an etiological diagnosis cannot be established with this procedure. However, in most patients, endoscopic ultrasonography can resolve these problems: to a fair degree of certainty, this technique can differentiate malignant from benign lesions, measure their size, and establish their layer of origin. Endoscopic ultrasonography is the technique of choice to establish the presence and characteristics of submucosal tumors and their suitability for treatment. Moreover, this procedure can identify tumors that can be removed endoscopically without excessive risk. Hydrogastric ultrasonography can be an effective substitute for echoendoscopy when evaluating submucosal lesions and for staging tumors of the gastric antrum when echoendoscopy is not available or in patients in whom it cannot be performed. Hydrogastric ultrasonography is safe, inexpensive and very well tolerated by patients. We present the case of a female patient with a gastric GIST that was evaluated using hydrogastric ultrasonography. The size, layer of origin, and malignancy of the tumor were accurately established.


Relationship of "don't know" responses to cancer knowledge and belief questions with colorectal cancer screening behavior.
Answering "I don't know" (DK) to survey questions that assess risk perceptions is common and occurs more often among disenfranchised groups. Because these groups also are at greater disease risk, statistically omitting or recoding DK responses may disproportionately exclude or misrepresent responses from marginalized groups and misinform intervention efforts. Because little is known about how the DK response is related to health behaviors, we examined whether the relation between DK response and colorectal cancer (CRC) screening behavior differed, depending on the construct queried (knowledge vs. beliefs). Data from the Awareness and Beliefs about Cancer survey of U.S. adults aged 50 years or older (N = 1406) were used. Cancer symptom knowledge, cancer beliefs, and CRC screening history were assessed. DK response options were not offered but were recorded if spontaneously provided. Logistic regression tested whether DK response on knowledge and belief scales were associated with CRC screening. Adjusting for demographic factors, responding DK on ≥1 belief item was associated with lower odds of having been screened for CRC in the last 5 years, p < .001, whereas DK response on ≥1 knowledge item was unassociated with screening, p = .48. DK responders to belief items were even less likely to have been screened than participants with negative beliefs about cancer, p = .011. DK responses are differentially associated with CRC screening, depending on the construct queried, suggesting different mechanisms may underlie DK responding or its relationship with screening. Addressing construct-specific causes of DK response may improve survey research and the interventions based on them. (PsycINFO Database Record


A case of ischemic colitis associated with the herbal food supplement ma huang.
Ischemic colitis is a condition that usually occurs in the elderly, as a form of vascular disease. However, ischemic colitis also occurs, though rarely, in healthy young adults. Moreover, food supplements containing Ephedra sinica or ma huang have been linked to adverse central nervous and cardiovascular events. A 40-year-old man was admitted to our emergency department after 2 episodes of abdominal pain and bloody diarrhea that lasted 24 hours. His medical history was unremarkable for risk factors of bowel ischemia, except for well-controlled hypertension. However, a weight-loss supplement, Ephedra sinica, had been prescribed for daily use during the previous month. Both abdominal/pelvic computed tomography and colonoscopy revealed findings compatible with ischemic colitis. His conditions spontaneously improved without any serious complications, and he was advised to discontinue the use of herbal medications containing ephedrine. In this paper, we describe a case of ischemic colitis that was potentially linked to the use of ma huang with a review of the relevant literature.


Desquamative gingivitis: a clinical, histopathologic, and immunologic study.
Desquamative gingivitis is believed to be a clinical sign of certain mucocutaneous diseases rather than a distinct pathologic entity. The prevalence of desquamative gingivitis was studied in a group of patients with the most common mucocutaneous diseases. Of 414 patients with pemphigus vulgaris, mucous membrane pemphigoid, or oral lichen planus, 49 (11.8%) exhibited gingival lesions in the form of desquamative gingivitis. Desquamative gingivitis was most prevalent in the patients with mucous membrane pemphigoid (41.6%) followed by those with pemphigus vulgaris (9.1%). Other clinical characteristics, as well as histopathologic and immunohistochemical findings, that aid in early diagnosis are presented.


Hydraulic flow characteristics in the lignotuberous mallee Eucalyptus behriana F. Muell. in the field.
The lignotuberous mallee Eucalyptus behriana F. Muell, had much lower predawn leaf water potentials (not higher than - 1.2MPa) than other eucalypts (as high as - 0.2MPa), even after extended rain. This led to the expectation that the lignotuber of E. behriana might have specific hydraulic characteristics. Keeping the soil around partially defoliated mallces for several days underwater did not raise the water status above the maximum leaf water potential observed under natural conditions. Digging a plant out and placing its roots in water after removal of the soil rapidly increased the water status to a level consistant with other eucalypts. This indicated that the major impedance to water uptake was a component of the soil rather than in the roots or in the lignotuber. Some of the individual mallces had only two major stems or branches. One stem or branch was kept covered throughout the experiments to prevent transpiration. The other stem was subjected to a variety of different conditions in order to modify water loss from it. The transpiring branch affected the water status of the non-transpiring plant parts. Hydraulic resistances in the shoot and root/lignotuber were determined from differences in the leaf water potential of covered and uncovered branches, at high water flow rates through the plant. Resistances in branches, including the liquid phase component of the leaf, were significantly larger than in root or lignotuber. The total plant hydraulic resistance of E. behriana was similar to that of other eucalypts, such as E. pauciflora Sieb. ex Spreng. or E. delegatensis R. T. Bak., even though its growth form was different and its natural leaf water potentials were much lower. An osmotic adjustment at the leaf level was observed in the mallee, keeping its bulk leaf turgor in the same range as compared to the other eucalypt species.


Protein-Polyelectrolyte Complexes and Micellar Assemblies.
In this review, we highlight the recent progress in our understanding of the structure, properties and applications of protein-polyelectrolyte complexes in both bulk and micellar assemblies. Protein-polyelectrolyte complexes form the basis of the genetic code, enable facile protein purification, and have emerged as enterprising candidates for simulating protocellular environments and as efficient enzymatic bioreactors. Such complexes undergo self-assembly in bulk due to a combined influence of electrostatic interactions and entropy gains from counterion release. Diversifying the self-assembly by incorporation of block polyelectrolytes has further enabled fabrication of protein-polyelectrolyte complex micelles that are multifunctional carriers for therapeutic targeted delivery of proteins such as enzymes and antibodies. We discuss research efforts focused on the structure, properties and applications of protein-polyelectrolyte complexes in both bulk and micellar assemblies, along with the influences of amphoteric nature of proteins accompanying patchy distribution of charges leading to unique phenomena including multiple complexation windows and complexation on the wrong side of the isoelectric point.


BAFF and CD4+ T cells are major survival factors for long-lived splenic plasma cells in a B-cell-depletion context.
Previous data have suggested that B-cell-depletion therapy may induce the settlement of autoreactive long-lived plasma cells (LLPCs) in the spleen of patients with autoimmune cytopenia. To investigate this process, we used the AID-CreERT2-EYFP mouse model to follow plasma cells (PCs) engaged in an immune response. Multiplex polymerase chain reaction at the single-cell level revealed that only a small fraction of splenic PCs had a long-lived signature, whereas PCs present after anti-CD20 antibody treatment appeared more mature, similar to bone marrow PCs. This observation suggested that, in addition to a process of selection, a maturation induced on B-cell depletion drove PCs toward a long-lived program. We showed that B-cell activating factor (BAFF) and CD4+ T cells play a major role in the PC survival niche, because combining anti-CD20 with anti-BAFF or anti-CD4 antibody greatly reduce the number of splenic PCs. Similar results were obtained in the lupus-prone NZB/W model. These different contributions of soluble and cellular components of the PC niche in the spleen demonstrate that the LLPC expression profile is not cell intrinsic but largely depends on signals provided by the splenic microenvironment, implying that interfering with these components at the time of B-cell depletion might improve the response rate in autoimmune cytopenia.


Clostridium perfringens Keratitis Leading to Blinding Panophthalmitis.
The purpose of this study was to report a case of Clostridium perfringens keratitis, which led rapidly to panophthalmitis, with loss of the eye in a healthy patient. Clinicopathologic case report, with a brief review of the literature. An otherwise healthy 50-year-old man without known risk factors developed a corneal ulcer, and within 48 hours, he lost all vision, with corneal perforation and panophthalmitis. The eye was enucleated, and the globe was examined histopathologically. The cornea was sampled for Gram staining and cultures, which revealed gram-positive rods and the growth of C. perfringens in the anaerobic culture. The globe revealed corneal necrosis and perforation, with acute inflammation in all layers of the eye. Gram-positive bacilli, consistent with C. perfringens, were identified in the vitreous cavity abscess. C. perfringens endophthalmitis cases from penetrating injuries are fulminant infections, with near universal loss of the eye, whereas C. perfringens keratitis cases are relatively indolent infections. To the best of our knowledge, this is the first report of a C. perfringens keratitis, which led rapidly to panophthalmitis. This aggressive behavior of C. perfringens has not been described previously in human subjects.


Action research: part 1. Achieving meaningful reflection.
The first article in the series explains the background to the study, outlying why action research was the methodology of choice and the literature that informed the study design. Part two will summarise the study process and consider the implications for practice.


Evolving Sex and Gender in Electronic Health Records.
Development, training, and documentation for the implementation of a self-identified gender identity field in the electronic health record system may improve patient-centered care for transgender and gender nonconforming patients.


An unexpected new tree species from Gansu, China: Illiciumgansuense (Schisandraceae).
We describe the newly-discovered species Illiciumgansuense (Schisandraceae), discovered in the Yuhe area of Giant Panda National Park, Gansu, China. Morphologically, I.gansuense resembles I.ternstroemioides and I.arborescens. However, the new species can be distinguished by its smaller leaf size, the larger number of tepals, tepal margin ciliate, and distinct flowering and fruiting seasons.


Cardiovascular medications in primary care: treatment gaps and targeting by absolute risk.
To measure the use of three major types of cardiovascular medications (antiplatelet, blood pressure lowering, and cholesterol lowering) in primary care, and their level of targeting to individuals at high absolute risk of a cardiovascular event. Demographic, risk factor, and prescribing data from the Dunedin Royal New Zealand College of General Practitioners Research Unit database were analysed. The data set consisted of 25,384 individuals, men aged at least 45 years and women at least 55 years, who consulted a doctor in 2000 in a practice which supplied electronic clinical notes. People with congestive heart failure were excluded. Five-year risk of a cardiovascular event was estimated using a history of vascular disease or the Framingham risk equation, and correlated with prescribed medications. Cardiovascular risk could be estimated for only one-third of the study population due to missing risk factor information. Data were largely unavailable on antiplatelet agents and so lipid lowering and blood pressure lowering medications were used to assess the 'treatment gap'. This combination was prescribed to only 28% of those with documented cardiovascular disease. For the remainder without a history of disease and for whom 5-year absolute risk of cardiovascular disease could be estimated, prescription of combination therapy ranged from 8% in the lowest risk group (<5% 5-year risk) to 14-16% in the other risk categories. Among this primary care population, more than two-thirds of people with vascular disease were not receiving guideline-recommended medications and there was little evidence of targeting by absolute risk for those without disease. However limited conclusions can be made for the latter group because of lack of documented risk factor information. While these treatment gaps may be less now, for example due to increased access to statins, it is probable that substantial gaps remain.


Successful treatment with eculizumab in a patient with pregnancy-associated atypical hemolytic uremic syndrome.
Pregnancy-associated atypical haemolytic uraemic syndrome is a rare and potentially lethal complement-mediated disorder. It can mimic preeclampsia, gestational hypertension, thrombotic thrombocytopenic purpura and hemolysis, elevated liver enzymes and low platelets syndrome. Thus, it can be hard to distinguish pregnancy-associated atypical haemolytic uraemic syndrome from other causes in peri/post-partum women presenting with features of microangiopathic haemolytic anemia, thrombocytopenia and acute kidney injury. We present a case of a 35-year-old woman in her third pregnancy at 32 weeks' gestation who underwent caesarean section due to fetal distress. She developed severe renal impairment, thrombocytopenia and neurologic symptoms within 24 hours after delivery. A diagnosis of pregnancy-associated atypical haemolytic uraemic syndrome was provided, and treatment with plasma therapy followed by eculizumab was initiated. A rapid improvement of both clinical and laboratory parameters was observed. This case demonstrates the significance of early initiation of anti-complement therapy to prevent irreversible renal damage and possible death in women with pregnancy-associated atypical haemolytic uraemic syndrome.


An Assessment of Thyroid Dysfunction and Related Parameters in Patients With Systemic Autoimmune Disorders.
Background and objective Systemic autoimmune disorders involve abnormal immune responses leading to tissue damage. Dysfunction of the thyroid gland due to autoimmune mechanisms is common in such disorders, which can cause either hypofunctioning or hyperfunctioning of the gland. This study aimed to investigate the prevalence of thyroid dysfunction among patients with various systemic autoimmune disorders. Material and methods This cross-sectional observational study included 110 adult patients either diagnosed with or having clinical/biological features of systemic autoimmune diseases. The patients underwent a detailed clinical history assessment, physical examination, and necessary investigations. Data were analyzed using IBM SPSS Statistics for Windows, Version 26.0. (IBM Corp., Armonk, NY). Results Among the 110 autoimmune disorder patients, 22.7% had thyroid dysfunction, specifically hypothyroidism, while 77.3% were euthyroid. Hypothyroidism was prevalent among patients with rheumatoid arthritis (RA, 20.3%), systemic sclerosis (SSc, 20%), ankylosing spondylitis (AS, 15.8%), and systemic lupus erythematosus (SLE, 54.5%). Moreover, 60% of patients were anemic, and the prevalence of anemia was higher among female patients and younger individuals. Conclusions This study showed a higher prevalence of thyroid dysfunction, particularly hypothyroidism, in patients with systemic autoimmune disorders. Female patients and younger individuals were more susceptible to autoimmune disorders, thyroid dysfunction, and anemia. These findings highlight the need for simultaneous screening and evaluation for thyroid dysfunction and anemia in systemic autoimmune disease patients, particularly in female patients and those of younger age groups.


All-Weather Solar Cells: A Rising Photovoltaic Revolution.
Solar cells have been considered as one of the foremost solutions to energy and environmental problems because of clean, high efficiency, cost-effective, and inexhaustible features. The historical development and state-of-the-art solar cells mainly focus on elevating photoelectric conversion efficiency upon direct sunlight illumination. It is still a challenging problem to realize persistent high-efficiency power generation in rainy, foggy, haze, and dark-light conditions (night). The physical proof-of-concept for all-weather solar cells opens a door for an upcoming photovoltaic revolution. Our group has been exploring constructive routes to build all-weather solar cells so that these advanced photovoltaic technologies can be an indication for global solar industry in bringing down the cost of energy harvesting. How the all-weather solar cells are built without reducing photo performances and why such architectures can realize electricity outputs with no visible-light are discussed. Potential pathways and opportunities to enrich all-weather solar cell families are envisaged. The aspects discussed here may enable researchers to develop undiscovered abilities and to explore wide applications of advanced photovoltaics.


Impact of Dietary Protein on the Management of Pediatric Short Bowel Syndrome.
Essential amino acids (AAs) play a key role in stimulating intestinal adaptation after massive small gut resection. The nutritional effect of dietary amino acids during intestinal regrowth has received considerable attention in recent years. This review explores the significance of dietary amino acids in the nutritional management of infants and children with intestinal failure and short bowel syndrome (SBS) as reported in the medical literature over the last three decades. A literature search was conducted using electronic databases. Breast milk emerged as the first-line enteral regimen recommended for infants with SBS. Hydrolyzed formulas (HFs) or amino acid formulas (AAFs) are recommended when breast milk is not available or if the infant cannot tolerate whole protein milk. The superiority of AAFs over HFs has never been demonstrated. Although glutamine (GLN) is the main fuel for enterocytes, GLN supplementation in infants with SBS showed no difference in the child's dependence upon parenteral nutrition (PN). Circulating citrulline is considered a major determinant of survival and nutritional prognosis of SBS patients. Early enteral nutrition and dietary supplementation of AAs following bowel resection in children are essential for the development of intestinal adaptation, thereby eliminating the need for PN.


Modelling-informed cell-seeded nerve repair construct designs for treating peripheral nerve injuries.
Millions of people worldwide are affected by peripheral nerve injuries (PNI), involving billions of dollars in healthcare costs. Common outcomes for patients include paralysis and loss of sensation, often leading to lifelong pain and disability. Engineered Neural Tissue (EngNT) is being developed as an alternative to the current treatments for large-gap PNIs that show underwhelming functional recovery in many cases. EngNT repair constructs are composed of a stabilised hydrogel cylinder, surrounded by a sheath of material, to mimic the properties of nerve tissue. The technology also enables the spatial seeding of therapeutic cells in the hydrogel to promote nerve regeneration. The identification of mechanisms leading to maximal nerve regeneration and to functional recovery is a central challenge in the design of EngNT repair constructs. Using in vivo experiments in isolation is costly and time-consuming, offering a limited insight on the mechanisms underlying the performance of a given repair construct. To bridge this gap, we derive a cell-solute model and apply it to the case of EngNT repair constructs seeded with therapeutic cells which produce vascular endothelial growth factor (VEGF) under low oxygen conditions to promote vascularisation in the construct. The model comprises a set of coupled non-linear diffusion-reaction equations describing the evolving cell population along with its interactions with oxygen and VEGF fields during the first 24h after transplant into the nerve injury site. This model allows us to evaluate a wide range of repair construct designs (e.g. cell-seeding strategy, sheath material, culture conditions), the idea being that designs performing well over a short timescale could be shortlisted for in vivo trials. In particular, our results suggest that seeding cells beyond a certain density threshold is detrimental regardless of the situation considered, opening new avenues for future nerve tissue engineering.


Genetic defects of steroidogenesis in premature pubarche.
Twenty three patients (19 girls, 4 boys) presented with typical features of premature pubarche between the ages of 2-7 yr. The patients were studied for the presence of an adrenal steroidogenic defect by ACTH stimulation testing (Cortrosyn, 0.25 mg iv bolus dose). Based on published nomogram standards for serum 17-hydroxyprogesterone (17-OHP), seven patients (30%) were diagnosed as having the nonclassical symptomatic form of 21-hydroxylase deficiency [mean post ACTH 4244 +/- 1113 (SD) ng/dl]. Three patients (13%) were diagnosed to have a mild form of 3 beta-hydroxysteroid dehydrogenase deficiency based upon the response of serum delta 5-17-hydroxypregnenolone (delta 5-17P) and dehydroepiandrosterone, and the ratio of delta 5-17P/17-OHP to ACTH stimulation (delta 5-17P: 1543 +/- 272 ng/dl vs. Tanner stage I control subjects, 350 +/- 197 ng/dl; dehydroepiandrosterone: 675 +/- 190 ng/dl vs. Tanner stage I control subjects, 82 +/- 79 ng/dl; delta 5-17P/17-OHP: 8.1 +/- 2.6 vs. Tanner stage I control subjects, 1.4 +/- 0.6). No enzyme defect could be identified in the remaining 13 patients (57%). Eleven patients with premature pubarche, with and without an adrenal enzymatic defect, underwent dexamethasone suppression. In all patients the measured steroid levels were suppressed. Thus, the dexamethasone suppression test alone did not distinguish the pathogenesis of premature pubarche. In conclusion, premature pubarche is more commonly due to a partial enzyme defect in adrenal steroidogenesis than has been previously recognized.


Routine viral load monitoring and enhanced adherence counselling at a public ART centre in Mumbai, India.
Routine viral-load (VL) measurements along with enhanced adherence counselling (EAC) are recommended to achieve virological suppression among people living with HIV/AIDS (PLHA) on anti-retroviral therapy (ART). The Mumbai Districts AIDS Control Society along with Médecins Sans Frontières has provided routine VL measurements and EAC to PLHA on ART at King Edward Memorial (KEM) hospital, Mumbai since October-2016. This study aims to describe the initial VL results and impact of EAC on viral suppression and factors associated with initial viral non-suppression among patients with an initial detectable VL, in a cohort of patients tested between October-2016 and September-2018. This is a descriptive study of PLHA on ART who received VL testing and EAC during October-2016 to September-2018. Log-binomial regression was used to identify factors associated with a high VL. Among 3849 PLHA who underwent VL testing, 1603(42%) were female and median age was 42 years (IQR:35-48). Majority were referred for routine testing (3432(89%)) and clinical/immunological failure (233(6%)). Overall, 3402(88%) PLHA had suppressed VL at initial testing. Among 3432 tested for routine monitoring, 3141(92%) had VL suppressed. Of 291 with VL>1000c/ml, 253(87%) received EAC and after repeat VL, 70(28%) had VL<1000c/ml. Among 233 referred for clinical/immunological failure, 122(52%) had VL>1000c/ml and 109 have been switched to second-line ART. CD4 count<500 (aOR-5.0[95%CI 3.8-6.5]), on ART for<5 years (aOR-1.5[1.1-2.0]) and age<15 years (aOR-5.2[3.0-8.9]) were associated with an initial VL>1000c/ml. Factors associated with follow-up VL suppression included EAC (p<0.05) and being on second-line ART (p<0.05). Results from a routine VL program in public sector in India were encouraging and in line with UNAIDS 90-90-90 targets. Routine VL monitoring along with EAC resulted in early switch to alternative optimised regimens while also preventing unnecessary switches. Along with the vital scale up of routine VL monitoring, implementation of enhanced adherence strategies for patients with detectable viral load should be ensured.


Effects of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and its analogues (EB1089 and analog V) on canine adenocarcinoma (CAC-8) in nude mice.
The aim of this study is to determine the effects of 1,25(OH)2D3 and its analogues on tumor growth and body weight, changes in plasma ionized calcium, parathyroid hormone-related protein (PTHrP) production, bone resorption, and the distribution of the 1,25(OH)2D3 receptor (VDR) on tumors in nude mice-bearing the canine adenocarcinoma (CAC-8). Thirty-seven nude mice were implanted subcutaneously with CAC-8. Two weeks after implantation, the mice were divided into 5 groups and injected intraperitoneally 3 times/week for 4 weeks with 5 different substrates. Group I (nontumor-bearing mice) were injected with vehicle. Groups II through V were CAC-8-bearing mice injected with the following: Grp. II, vehicle; Grp. III, analog V; Grp. IV, 1,25(OH)2D3; and Grp. V, EB1089. Our results showed that mice body weight (% change) of CAC-8-bearing mice was significantly lower than those of nontumor-bearing mice (p<0.05). CAC-8-bearing mice treated with analog V maintained their body weight better than CAC-8-bearing mice treated with either vehicle, 1,25(OH)2D3, or EB1089. A reduction of tumor growth was observed in CAC-8-bearing mice treated with 1,25(OH)2D3 and its analogues; however, the reduction was not statistically significant compared to the vehicle-treated CAC-8-bearing mice. All CAC-8-bearing mice increased osteoclastic bone resorption and hypercalcemia. Immunohistochemical staining of CAC-8 with VDR antibody demonstrated a positive reaction in nuclei of tumor cells. In conclusion, CAC-8-bearing mice treated with analog V were more active and maintained their body weight better than other CAC-8-bearing groups. Analog V-treated mice also showed no toxic side effects of hypercalcemia despite an increase in plasmaionized calcium comparable to nontumor-bearing mice. Tumor volumes of CAC-8-bearing mice treated with 1,25(OH)2D3 and its analogues were smaller than vehicle-treated CAC-8-bearing mice. This finding suggested an inhibitory effect on tumor cell growth.


Prevalence and predictive factors for depressive symptoms among medical students in Germany - a cross-sectional study.
Background: Elevated levels of depressive symptoms among medical students have been the subject of international and national research before, yet associated risk factors and protective factors are to be determined. This study aims to show the burdens of depression at different stages of academic medical education with a special emphasis on correlated risk factors and protective factors. Methods: A total number of n=1103 medical students of a middle-sized German university were sampled and surveyed regarding depressive symptoms and correlating factors. The assessment of potential depressive symptoms was based on the BDI-II. Correlating factors were surveyed through a self-designed questionnaire consisting of possible cofactors for depressive symptoms based on established scientific literature. Results: Survey response rate was 90.2% (1103/1223). The prevalence of depressive symptoms was 11% for mild, 5.6% for moderate and 2.4% for severe symptoms. The sample's most prevalent risk factors were feeling unable to confide one's own worries to someone else (88%); and experiencing a lack of time for partner, friends and family (77%) or hobbies (76%). Significant predictors for depressive symptoms were neuroticism above all, insufficient emotional support, eating irregular meals, use of medication or drugs to calm down, and mental overload. Factors associated with less depressive symptoms could be identified as: spending time with partner, friends, family, hobbies and exercise; and confiding worries to classmates. Conclusions: Every fifth medical student surveyed reported at least mild depressive symptoms. The majority of the surveyed medical students felt unable to confide their worries to someone else and lamented not having enough time for social interaction with peers, family and hobbies. Certain personality traits - such as neuroticism - and insufficient emotional support showed to play important roles in making medical students more prone to developing depressive symptoms. Based on this research, control of the surveyed cofactors associated with depressive symptoms and possible intervention programs targeted to these are proposed to be a key subject of further research.


Recurrent gallstone ileus: case report and literature review.
The gallstone ileus is a rare complication of cholelithiasis and it represents the 1-4% of small intestinal mechanical obstruction. Gallstone is generally wedged in the terminal ileum, even if unusual locations have been described. The literature reports a very high morbidity and mortality, often because misdiagnosis or delayed diagnosis. There is no unique opinion in literature about the choice between one-stage and two-stage surgery. We report a clinical case that summarizes the diagnostic and therapeutic difficulties of gallstone ileus.


Identification of a mitochondrial alcohol dehydrogenase in Schizosaccharomyces pombe: new insights into energy metabolism.
In the present study we have shown that mitochondria isolated from Schizosaccharomyces pombe exhibit antimycin A-sensitive oxygen uptake activity that is exclusively dependent on ethanol and is inhibited by trifluoroethanol, a potent inhibitor of ADH (alcohol dehydrogenase). Ethanol-dependent respiratory activity has, to our knowledge, not been reported in S. pombe mitochondria to date, which is surprising as it has been concluded previously that only one ADH gene, encoding a cytosolic enzyme, occurs in this yeast. Spectrophotometric enzyme assays reveal that ADH activity in isolated mitochondria is increased approximately 16-fold by Triton X-100, which demonstrates that the enzyme is located in the matrix. Using genetic knockouts, we show conclusively that the novel mitochondrial ADH is encoded by adh4 and, as such, is unrelated to ADH isoenzymes found in mitochondria of other yeasts. By performing a modular-kinetic analysis of mitochondrial electron transfer, we furthermore show how ethanol-dependent respiratory activity (which involves oxidation of matrix-located NADH) compares with that observed when succinate or externally added NADH are used as substrates. This analysis reveals distinct kinetic differences between substrates which fully explain the lack of respiratory control generally observed during ethanol oxidation in yeast mitochondria.


Stoichiometric network constraints on xylose metabolism by recombinant Saccharomyces cerevisiae.
Metabolic pathway engineering is constrained by the thermodynamic and stoichiometric feasibility of enzymatic activities of introduced genes. Engineering of xylose metabolism in Saccharomyces cerevisiae has focused on introducing genes for the initial xylose assimilation steps from Pichia stipitis, a xylose-fermenting yeast, into S. cerevisiae, a yeast traditionally used in ethanol production from hexose. However, recombinant S. cerevisiae created in several laboratories have used xylose oxidatively rather than in the fermentative manner that this yeast metabolizes glucose. To understand the differences between glucose and engineered xylose metabolic networks, we performed a flux balance analysis (FBA) and calculated extreme pathways using a stoichiometric model that describes the biochemistry of yeast cell growth. FBA predicted that the ethanol yield from xylose exhibits a maximum under oxygen-limited conditions, and a fermentation experiment confirmed this finding. Fermentation results were largely consistent with in silico phenotypes based on calculated extreme pathways, which displayed several phases of metabolic phenotype with respect to oxygen availability from anaerobic to aerobic conditions. However, in contrast to the model prediction, xylitol production continued even after the optimum aeration level for ethanol production was attained. These results suggest that oxygen (or some other electron accepting system) is required to resolve the redox imbalance caused by cofactor difference between xylose reductase and xylitol dehydrogenase, and that other factors limit glycolytic flux when xylose is the sole carbon source.


Quantification of amplified quenching for conjugated polymer microsphere systems.
A series of nonaggregating carboxylate-functionalized poly(phenylene ethynylene)s (PPEs) have been synthesized for immobilization via electrostatic adsorption onto Eu3+-polystyrene microspheres with a mean diameter of 0.2 microm. This system is shown to constitute a ratiometric system that measures fluorescence quenching with high fidelity. The fluorescence quenching properties of the polymer-coated particles in response to methyl viologen and a naphthyl-functionalized viologen have been investigated in aqueous solutions to study the influence of electrostatic and hydrophobic interactions with pentiptycene-incorporated as well as macrocycle-containing polymers.


The Association Between Structural, Performance, and Community Factors and the Likelihood of Receiving a Penalty Under the Hospital Readmissions Reduction Program (Fiscal Year 2013-2019).
Purpose: Little is known about the role of structural, performance, and community factors that impact the likelihood of receiving a penalty under the Hospital Readmission Reduction Program. This study examined the association between structural, performance, and community factors and the likelihood of receiving a penalty as well as investigated the likelihood of hospitals serving vulnerable populations of receiving a penalty. Methods: Centers for Medicare and Medicaid Services and United States Census Bureau data were used in this analysis. Ordered logistic regressions in a cross-sectional analysis were employed to estimate the probability of receiving a high or low penalty in the fiscal year 2013 through 2019. Results: On average, medium-sized, major teaching, and safety-net hospitals had the highest proportion of hospitals with a high penalty. After controlling for performance and community factors, structural factor variables such as safety-net status, rural status, and teaching status either were no longer significant or the likelihood magnitude changed. However, after controlling for performance and community factors, the statistical significance of hospital size variables and geographic location persisted across the years. Length of stay and occupancy rate variables were also statistically significant across the 7 years under review. Conclusion: Taken together, structural, performance, and community factors are important in explaining variation in the likelihood of receiving a penalty. There is no evidence that safety-net, rural, and public hospitals are more likely to receive a penalty. The results also suggest that there is room for providers to reduce avoidable readmissions and policymakers to mitigate unintended consequences.


Comparative phenotype mapping of normal vs. malignant pediatric B-lymphopoiesis unveils leukemia-associated aberrations.
Leukemic cells of B-lineage acute lymphoblastic leukemia (ALL) are regarded as the malignant counterparts of immature, physiologic B cell precursors (BCPs). To determine whether phenotypic differences exist between these corresponding cell types, we investigated samples of normal pediatric bone marrow (n=30) as well as of B-precursor ALL at diagnosis (n=53; common and pre-B subtype). Using three-color multiparameter flow cytometric analysis, we compared the leukemic populations with the physiologic BCPs of corresponding maturity with respect to the intensity with which they expressed a series of antigens. In some of these antigens, leukemia-associated aberrations were frequently observed. In particular, overexpression of CD10 was displayed by 65% of ALL samples, whereas 58% of leukemic cases aberrantly exhibited very low or no CD45RA expression. Regarding CD11a and CD44, 47% and 35% of ALL populations were aberrant as defined by either the absence or significant overexpression of the antigen. In contrast, antigen densities of CD49d, CD49e, and CD99 on leukemic cells were in the normal range of values for BCPs. Combining the patterns of frequently aberrant markers in a comprehensive analysis, we were able to identify individual phenotypic leukemic cell aberrations in up to 98% of investigated cases. CD10 and/or CD45RA were aberrant in 86% of cases overall, emphasizing the high discriminative potential of these two markers. Using comparative phenotype mapping based on quantitatively aberrant, leukemia-associated antigenic patterns, we were able to detect leukemic blasts among normal bone marrow cells at frequencies as low as 10(-5). We speculate that our approach may have a profound impact on the development of new strategies for minimal residual disease investigations in patients with BCP-ALL.


Cross-Linking Furan-Modified Kisspeptin-10 to the KISS Receptor.
Chemical cross-linking is well-established for investigating protein-protein interactions. Traditionally, photo cross-linking is used but is associated with problems of selectivity and UV toxicity in a biological context. We here describe, with live cells and under normal growth conditions, selective cross-linking of a furan-modified peptide ligand to its membrane-presented receptor with zero toxicity, high efficiency, and spatio-specificity. Furan-modified kisspeptin-10 is covalently coupled to its glycosylated membrane receptor, GPR54(KISS1R). This newly expands the applicability of furan-mediated cross-linking not only to protein-protein cross-linking but also to cross-linking in situ. Moreover, in our earlier reports on nucleic acid interstrand cross-linking, furan activation required external triggers of oxidation (via addition of N-bromo succinimide or singlet oxygen). In contrast, we here show, for multiple cell lines, the spontaneous endogenous oxidation of the furan moiety with concurrent selective cross-link formation. We propose that reactive oxygen species produced by NADPH oxidase (NOX) enzymes form the cellular source establishing furan oxidation.


Extraintestinal manifestations in a large series of Italian inflammatory bowel disease patients.
To investigate prevalence, type and time of onset of extraintestinal manifestations (EIMs) in a series of Italian inflammatory bowel disease (IBD) patients. Data of 811 IBD consecutive patients, first referred to our Centre from 2000 to 2011, were retrospectively evaluated. Eight hundred and eleven IBD patients (437 M, 374 F) were studied: 595 ulcerative colitis (UC) (73.4%) and 216 Crohn's disease (CD) (26.6%). Among these, 329 (40.6%) showed EIMs: 210 UC (35.3%) and 119 CD (55.1%) (P < 0.0001). Considering the time of the diagnosis of IBD, 37 EIMs (11.2%) were developed before, 229 (69.6%) after and 63 (19.2%) were simultaneous. The type of EIM were as follows: 240 musculoskeletal (29.6%), in 72 CD patients and in 168 UC (P < 0.0001); 47 mucocutaneous (5.8%), in 26 CD and in 21 UC (P = 0.0049); 26 ocular (3.2%), in 16 CD and in 10 UC (CD 7.4% vs UC 1.7%, P = 0.0093); 6 hepatobiliary (0.8%); 10 endocrinological (1.2%). In particular, with regards to the involvement of the musculoskeletal system, arthritis Type 1 was found in 41 CD (19%) and in 61 UC (10.2%) (P = 0.0012) and Type 2 in 25 CD (11.6%) and in 100 UC (16.8%) (P = 0.0012). Mucocutaneous manifestations, arthritis Type 1 and uveitis were significantly more frequent in CD than UC. The complications of the musculoskeletal system were the mostly observed ones, often with symptoms more severe than intestinal ones, confirming the need for close cooperation with rheumatologists.


The determination of child custody.
This article reviews briefly the history of child custody decision making and describes current custodial arrangements in the United States. It examines both the manner in which parents and courts make decisions regarding custody and access, and the changes in visiting patterns in recent decades. The author discusses the impact of reforms in the law and the implementation of newer dispute resolution and educational interventions, and then makes recommendations for policy and practice.


Immunogenic proteins of feline rhinotracheitis virus.
Feline rhinotracheitis virus is an upper-respiratory-tract pathogen of cats. It may also cause generalized infections or abortions. Antigens present in [35S]methionine- or [14C]glucosamine-labeled purified virions, in Nonident P-40 (NP-40) extracts of a mixture of virions and infected cells, and in virion-free cell culture medium, along with mock-infected Crandell -Rees feline kidney cell controls, were analyzed by direct sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) or by SDS-PAGE preceded by Staphylococcus aureus protein A immunoprecipitation. The direct SDS-PAGE analysis revealed at least 17 virus-specific peptides with molecular weights ranging from less than 200,000 ( 200K ) to more than 30K . Three of these peptides were glycosylated and had molecular weights of 105K , 68K , and 60K. Immunoprecipitates of purified virions and NP-40 extracts contained three major glycoproteins with the same estimated molecular weights as those found by the direct analysis. A prominent 105K glycoprotein was present in virion-free cell culture medium immunoprecipitates. In addition, a number of nonglycosylated feline rhinotracheitis virus-specific polypeptides (eight in virions, three in NP-40 extracts, and nine in virion-free cell culture medium), ranging in molecular weight from 145K to 32K, were present in the various immunoprecipitates.


N-acetylcysteine alleviates cadmium-induced placental endoplasmic reticulum stress and fetal growth restriction in mice.
Cadmium (Cd) is a developmental toxicant that induces fetal growth restriction (FGR). Placental endoplasmic reticulum (ER) stress is associated with FGR. This study investigated the effects of N-acetylcysteine (NAC) on Cd-induced placental ER stress and FGR. Pregnant mice were intraperitoneally injected with CdCl2 daily from gestational day (GD)13 to GD17. As expected, Cd reduced fetal weight and crown-rump length. Cd decreased the internal space of blood vessels in the placental labyrinth layer and inhibited placental cell proliferation. Several genes of growth factors, such as Vegf-a, placental growth factor, Igf1 and Igf1r, and several genes of nutrient transport pumps, such as Glut1, Fatp1 and Snat2, were down-regulated in placenta of Cd-treated mice. Moreover, Cd evoked placental ER stress. Of interest, NAC alleviated Cd-induced FGR. Additional experiment showed that NAC inhibited Cd-induced impairment of placental development and placental ER stress. Therefore, NAC may be exploited for prevention of Cd-induced placental insufficiency and FGR.


Exopolysaccharide Production by Sinorhizobium fredii HH103 Is Repressed by Genistein in a NodD1-Dependent Manner.
In the rhizobia-legume symbiotic interaction, bacterial surface polysaccharides, such as exopolysaccharide (EPS), lipopolysaccharide (LPS), K-antigen polysaccharide (KPS) or cyclic glucans (CG), appear to play crucial roles either acting as signals required for the progression of the interaction and/or preventing host defence mechanisms. The symbiotic significance of each of these polysaccharides varies depending on the specific rhizobia-legume couple. In this work we show that the production of exopolysaccharide by Sinorhizobium fredii HH103, but not by other S. fredii strains such as USDA257 or NGR234, is repressed by nod gene inducing flavonoids such as genistein and that this repression is dependent on the presence of a functional NodD1 protein. In agreement with the importance of EPS for bacterial biofilms, this reduced EPS production upon treatment with flavonoids correlates with decreased biofilm formation ability. By using quantitative RT-PCR analysis we show that expression of the exoY2 and exoK genes is repressed in late stationary cultures of S. fredii HH103 upon treatment with genistein. Results presented in this work show that in S. fredii HH103 EPS production is regulated just in the opposite way than other bacterial signals such as Nod factors and type 3 secreted effectors: it is repressed by flavonoids and NodD1 and enhanced by the nod repressor NolR. These results are in agreement with our previous observations showing that lack of EPS production by S. fredii HH103 is not only non-detrimental but even beneficial for symbiosis with soybean.


Development of a chemotherapeutic model for microfilaricidal drugs to Dirofilaria immitis.
Microfilariae obtained from in vitro culture of adult Dirofilaria immitis were inoculated into naive dogs and used to test the in vivo efficacy of the antimicrofilarial drug Dizan. Injection of 33 million microfilariae into a 3-month-old male beagle pup over a 5-day period resulted in a microfilaremia that peaked at 863 microfilariae per ml on day 30. Treatment with Dizan resulted in a rapid clearance of microfilariae from the peripheral circulation. Four additional male beagle pups that were each given a total of 31 million microfilariae over 100 days maintained an average of 25 microfilariae per ml for 2 months. Microfilaremias were monitored by ELISA, a modified Knott's method and selected blood chemistry tests. It was shown that after residing in the peripheral circulation the microfilariae were able to develop into infective larvae in mosquitoes; therefore, the system may be a reasonable model of the natural microfilaremic state.


Batch Selection via In Vitro/In Vivo Correlation in Pharmacokinetic Bioequivalence Testing.
Pharmacokinetic differences between manufacturing batches, well established for inhaled drug products, preclude control of patient risk in the customary two-way (single batch) pharmacokinetic bioequivalence crossover design if batches are randomly chosen. European regulators have recommended selecting a "typical" in vitro batch to represent each product in pharmacokinetic bioequivalence testing. We explored the feasibility of this approach to control patient risk (the "false equivalence", or Type I, error rate). The probability of achieving a Test/Reference 90% confidence interval within (0.80, 1.25) for a true (non-equivalent) value of 1.25 was simulated for a two-way crossover design using the median in vitro batch across a range of number of in vitro batches, in vitro/in vivo correlation (IVIVC) quality (correlation coefficient, r, of zero to one), and within-subject between-batch pharmacokinetic variability. Even under extremely optimistic conditions, e.g., r=0.95 and >100 batches per product screened in vitro, patient risk for typical between-batch variability levels remained at least threefold higher than the 5% regulatory expectation for the significance level (the false equivalence error rate) of the pharmacokinetic bioequivalence test. This elevated error rate in bioequivalence decision-making occurs because of incomplete confidence that the true product average has been identified, and, importantly, omission of this uncertainty from the bioequivalence confidence interval.


Diets and living conditions of Asian boys in Coventry with and without signs of rickets.
1. The diets and living conditions of nin Asian boys with biochemical, and in most instances also radiological, signs of rickets were compared with those of nine other boys who appeared to be normal. The groups were matched according to age, religion, place of father's origin and boy's own place of birth. 2. There were no outstanding differences between the diets of the boys with, and of those without signs of rickets. All had adequate to high calcium intakes. Most of the boys had low intakes of vitamin D, and those withsigns of rickets generally had lower intakes than the normal boys. The food tables used for making the calculations of vitamin D intakes report the amount of the vitamin in the lipid fraction of milk. If it proves to be true that most of the vitamin D activity of milk is in the aqueous fraction, the boys would have been getting considerably more vitamin D than the results suggested, and their average intake may have been about 3-5mug/d. 3. It was not possible to make any quantitative measure of the exposure of the boys to sunlight. All Asian boys studied appeared to have their bodies more completely covered than British or West Indian boys. 4. The problem of why nine boys had signs of rickets and nine had none has not been solved. It is suggested that those with signs of rickets may have had higher requirements for vitamin D than others. When the intake of vitamin D is low and exposure to sunlight is minimal, those with high requirements will be the ones to develop signs of rickets.


[Alternative treatment of patients with rheumatism. The extent, effect and utilization of resources].
An anonymous questionnaire investigation involving 393 rheumatological patients showed that 185 patients (47%) had tried alternative treatment (52% of the women and 33% of the men). The three forms of treatment most commonly employed were chiropractor treatment, zone therapy and acupuncture. The 185 patients had, on an average, tried 2.2 types of treatment and 30% had tried more than two forms of treatment. One third of the patients had tried alternative treatment before or simultaneously with medical treatment while the remaining 2/3 had received medical treatment from weeks up to several years. The sources of information about alternative treatment were, most frequently, friends and relatives (70%) while in 16%, the general practitioner was the source. Only 58% replied to the question about the effect of the alternative treatment. Out of these, 56% had experienced improvement, 41% stated that there was no effect and 2% stated that deterioration had occurred. On an average, the patients had employed 2,444 Danish crows (approximately 200 pounds) for the alternative treatment. In addition, 6% stated that had spent more than 10,000 Danish crowns (approximately 833 pounds). It is concluded that alternative treatment frequently constitutes a considerable economical stress for the patients. Greater frankness and a increased level of information about the alternative forms of treatment are necessary.


Receptor reserve and turnover of alpha-2 adrenoceptors that mediate the clonidine-induced inhibition of rat locus coeruleus neurons in vivo.
The population of reserve alpha-2 adrenoceptors that mediate the inhibitory effect of clonidine on the activity of locus coeruleus neurons has been studied using extracellular recordings in anesthetized rats. Animals were pretreated with the irreversible receptor antagonist N-ethoxycarbonyl-2-ethoxy-1-2-dihydroquinoline (EEDQ). In rats pretreated with EEDQ (1, 2 and 6 mg/kg, i.p., 6 hr before experiment), there was an increase in firing rate, a reduction in firing regularity (i.e., increased variation coefficient) and an increase in burst firing of locus coeruleus neurons. Partial receptor inactivation with EEDQ (1 and 2 mg/kg, i.p.) caused a dose-dependent shift to the right of dose-effect curves for i.v. administered clonidine together with a reduction in its maximal effect. Higher doses of EEDQ (6 mg/kg, i.p.) completely abolished the effect induced by clonidine. This blockade was associated with a progressive decrease in the number of remaining receptors (noninactivated receptors). The pseudo-constant of dissociation for the drug-receptor complex was calculated to be approximately 70 micrograms/kg. The receptor occupancy-effect relationship was hyperbolic giving a value of only approximately 4% occupancy at 50% maximal effect. Estimates of noninactivated receptors and percentage of receptor occupancy at 50% of maximal effect were comparable when locally administered clonidine was used. After complete receptor inactivation with EEDQ (6 mg/kg), dose-effect curves for clonidine recovered gradually. The inhibitory effect of clonidine returned faster (half-life = 14 hr) than the receptor pool (half-life = 37 hr). These results indicate that locus coeruleus neurons have a large reserve of alpha 2 adrenoceptors that in addition, are rapidly turned over.


Meta-generalized gradient approximation: explanation of a realistic nonempirical density functional.
Tao, Perdew, Staroverov, and Scuseria (TPSS) have constructed a nonempirical meta-generalized gradient approximation (meta-GGA) [Phys. Rev. Lett. 91, 146401 (2003)] for the exchange-correlation energy, imposing exact constraints relevant to the paradigm densities of condensed matter physics and quantum chemistry. Results of their extensive tests on molecules, solids, and solid surfaces are encouraging, suggesting that this density functional achieves uniform accuracy for diverse properties and systems. In the present work, this functional is explained and details of its construction are presented. In particular, the functional is constructed to yield accurate energies under uniform coordinate scaling to the low-density or strong-interaction limit. Its nonlocality is displayed by plotting the factor F(xc) that gives the enhancement relative to the local density approximation for exchange. We also discuss an apparently harmless order-of-limits problem in the meta-GGA. The performance of this functional is investigated for exchange and correlation energies and shell-removal energies of atoms and ions. Non-self-consistent molecular atomization energies and bond lengths of the TPSS meta-GGA, calculated with GGA orbitals and densities, agree well with those calculated self-consistently. We suggest that satisfaction of additional exact constraints on higher rungs of a ladder of density functional approximations can lead to further progress.


Long noncoding RNA transcriptome analysis reveals novel lncRNAs in Morus alba 'Yu-711' response to drought stress.
Drought stress has been a key environmental factor affecting plant growth and development. The plant genome is capable of producing long noncoding RNAs (lncRNAs). To better understand white mulberry (Morus alba L.) drought response mechanism, we conducted a comparative transcriptome study comparing two treatments: drought-stressed (EG) and well-watered (CK) plants. A total of 674 differentially expressed lncRNAs (DElncRNAs) were identified. In addition, 782 differentially expressed messenger RNAs (DEmRNAs) were identified. We conducted Gene Ontology (GO) and KEGG enrichment analyses focusing on the differential lncRNAs cis-target genes. The target genes of the DElncRNAs were most significantly involved in the biosynthesis of secondary metabolites. Gene regulatory networks of the target genes involving DElncRNAs-mRNAs-DEmRNAs and DElncRNA-miRNA-DEmRNA were constructed. In the DElncRNAs-DEmRNAs network, 30 DEmRNAs involved in the biosynthesis of secondary metabolites are collocated with 46 DElncRNAs. The interaction between DElncRNAs and candidate genes was identified using LncTar. In summary, quantitative real-time polymerase chain reaction (qRT-PCR) validated nine candidate genes and seven target lncRNAs including those identified by LncTar. We predicted that the DElncRNAs-DEmRNAs might recruit microRNAs (miRNAs) to interact with gene regulatory networks under the drought stress response in mulberry. The findings will contribute to our understanding of the regulatory functions of lncRNAs under drought stress and will shed new light on the mulberry-drought stress interactions.


Ca2+ sensitivity of Ca2+-dependent protein kinase activities toward intrinsic proteins in synaptosomal membrane fragments from rat cerebral tissue.
The Ca2+ and calmodulin sensitivity of endogenous protein kinase activity in synaptosomal membrane fragments from rat brain was studied in medium containing Ca2+ plus EGTA using a modified computer programme to calculate free Ca2+ concentrations that took into account the effect of all competing cations and chelators. The Ca2+-dependent phosphorylation of 10 major polypeptide acceptors with Mr values ranging from 50 to 360 kilodaltons required calmodulin in reactions that were all equally sensitive to Ca2+; half-maximal phosphorylation required a free Ca2+ concentration of 45 nM and maximal phosphorylation approximately 110 nM. The significance of these values in relation to published data on the intracellular concentration of free Ca2+ in the nervous system is discussed. One acceptor of 45 kilodaltons was phosphorylated in a Ca2+-dependent reaction that did not require calmodulin. This polypeptide appeared to correspond to the B-50 protein, an established substrate of the lipid-dependent protein kinase C. Further study of this phosphorylating system showed that the reaction was only independent of calmodulin at saturating concentrations of Ca2+; at subsaturating concentrations (in the range 50-130 nM), a small but significant stimulation of the enzyme by calmodulin was demonstrated. The possible significance of this finding is discussed.


Tunable electrical contact properties in two-dimensional van der Waals V2C/MoSi2N4heterostructures.
Two-dimensional MoSi2N4is a member of the emerging 2D MA2N4family, which has been synthesized in experiments, recently. Herein, we conduct a first-principles investigation to study more about the atomic and electronic structures of V2C/MoSi2N4(1T-phase) van der Waals heterostructures (vdWHs) and interlayer distance and an external perpendicular electric field change their tunable electronic structures. We demonstrate that the V2C/MoSi2N4vdWHs contact forms n-type Schottky contact with an ultralow Schottky barrier height of 0.17 eV, which is beneficial to enhance the charge injection efficiency. In addition, the electronic structure and interfacial properties of V2C/MoSi2N4vdWHs can be transformed from n-type to p-type ShC through the effect of layer spacing and electric field. At the same time, the transition from ShC to OhC can also occur by relying on the electric field and different interlayer spacing. Our findings could give a novel approach for developing optoelectronic applications based on V2C/MoSi2N4vdW heterostructures.